Does this patient have autosomal dominant polycystic disease?

Autosomal dominant polycystic kidney disease (ADPKD) is a systemic disease characterized by cyst formation in the kidneys and a spectrum of extrarenal manifestations with variable penetrance. Cyst growth and expansion occurs throughout the patient’s lifetime, resulting in progressive renal enlargement, renal insufficiency and ultimately renal failure usually in the 6th decade of life. ADPKD is one of the most common genetic diseases in humans, occurring in 1:700-1:1000 individuals.

ADPKD is a dominantly inherited disorder that does not skip a generation (Figure 1) and every offspring of an affected individual has a 50% chance of inheriting the gene.

Figure 1.

Pedigree of a family affected with autosomal dominant polycystic kidney disease.

PKD1, one of the genes responsible for ADPKD, was identified in 1994 on the short arm of chromosome 16 next to the TSC2 gene in a Portuguese family with both autosomal dominant polycystic kidney disease (ADPKD) and tuberous sclerosis complex (TSC). A second ADPKD gene, PKD2, was subsequently identified in the long arm of chromosome 4 in 1996. Mutations in PKD1 and PKD2 are causative in about 85% and 15% of cases of ADPKD, respectively. In very few cases, no mutation can be found on the PKD1 or PKD2 locus. A third gene locus causing autosomal dominant polycystic kidney (and liver) disease was recently identified, and involves the GANAB gene, encoding the ER-resident glucosidase II, subunit α. Other loci remain unknown, but contribute very little to the global prevalence of ADPKD.

The resulting disease phenotypes are identical in PKD1 and PKD2 patients, except that patients with PKD2 mutations have milder symptoms on average: age of onset of hypertension is 10 years later, mean age of onset of end-stage renal disease (ESRD) is 74 vs. 55 years, and life expectancy is greater in PKD2 individuals by approximately 10 years.

Small renal cysts exist from early stages of fetal development on, but continue to grow throughout a lifetime. Small cysts are unlikely to cause symptoms, and patients with ADPKD may live asymptomatically for many years. The most common renal symptoms that occur in ADPKD patients include hypertension, pain, gross hematuria, kidney stones and urinary tract infections. Pain can be acute, from cyst rupture, hemorrhage or infection, or chronic, from the mass effect of very large cystic kidneys. Patients describe increased abdominal girth, abdominal fullness, early satiety, nausea and back pain. In later stages, thirst, urinary frequency, nocturia and abdominal pain are the most significant concerns.

Patients may also experience symptoms from extrarenal manifestations that include intracranial aneurysms, cystic disease of liver and pancreas, cardiac valvular disease (most commonly mitral valve prolapse), colonic diverticulosis, as well as infertility, related to seminal vesical cysts. ADPKD patients who progress to ESRD require kidney transplant or either peritoneal or hemodialysis.

On physical exam, characteristic findings include increased blood pressure on average by 30 years of age, including 20% of affected children, palpable kidneys, increased abdominal girth, ventral and inguinal hernias, and auscultatory abnormalities related to cardiac valve diseases such as mitral valve prolapse or aortic insufficiency.

Multiple cysts found in the kidney may due to inherited or acquired circumstances. Among the inherited renal cystic diseases, ADPKD, HNF-1β related kidney disease, tuberous sclerosis complex (TSC), medullary cystic kidney disease (MCKD) and von Hippel-Lindau disease (VHL) are passed down in autosomal dominant manner; autosomal recessive diseases, including autosomal recessive polycystic kidney disease (ARPKD) and familial juvenile nephronopthisis (FJN), are less common and present in a single generation of affected individuals. Acquired cystic kidney disease (ACKD) is the most common non-hereditary cystic disease, usually occurring in patients (either adults or children) with long term renal insufficiency, especially dialysis patients.

Renal cysts are a manifestation of many syndromatic diseases. For example, the coexistence of renal cysts and angiomyolipomas is characteristic for tuberous sclerosis complex (TSC). VHL is primarily a tumor syndrome involving retina, cerebellum, adrenal glands, kidneys and other organs. Its renal cysts are not necessarily associated with coexisting clear cell carcinomas. When other tumors are absent, the VHL kidney may appear similar to mild or early ADPKD. Mutations in the HNF-1β gene manifest in a multitude of different phenotypes, that may or may not involve maturity-onset diabetes of the young (MODY-5), hepatic and pancreatic abnormalities, autism, CAKUT-spectrum abnormalities and polycystic kidneys, sometimes identical with PKD1/2 mutations.

Approximately 15% of ADPKD patients do not have a positive family history for the disorder. In these individuals, ultrasonographic screening of the parents if possible is recommended. In some individuals, this could be a mild disease where the affected parent is asymptomatic. For those where parents have been screened and are negative, ADPKD may have resulted from parental mosaicism, spontaneous de-novo mutation or uncertain biological paternity.

Isolated polycystic liver disease (PCLD) is an inherited autosomal dominant liver disease. In cases of PCLD without renal involvement, the disease presents liver enlargement due to fluid-filled cysts derived from the biliary system. Mutations in the genes PRKCSH, SEC63 and LRP5 have been identified as genetic causes of ADPLD. Mutations in the recently identified GANAB gene that are causative in rare PKD1-negative, PKD2-negative ADPKD, give rise to polycystic liver phenotypes as well, emphasizing that ADPKD and PCLD represent one spectrum of diseases with significant genotypic and phenotypic overlap. Interestingly, PRKCSH and GANAB encode for two different (α-, β-) subunits of the same enzyme, glucosidase-II. Along with the SEC63 gene product, they play a biological role along the same ER-secretory pathway.

What tests to perform?

Urinalysis

ADPKD urine sample is usually bland, not significant for proteinuria or hematuria. Very low amounts of protein may be present on urine dipstick. Only 25% of adults and 32% of children have dipstick detectable proteinuria. Hematuria is atypical in ADPKD and when present it suggests hemorrhagic cyst, infection, uroepithelial lesion, or possible kidney stone. Further investigation, including imaging utilizing ultrasound or computed tomography (CT) may be necessary.

Plasma or serum analyses

Complete blood count (CBC), platelets and comprehensive chemistry panels with phosphorus provide all biochemical information, such as electrolytes, creatinine, phosphate, and parathyroid hormone levels. 25(OH)-Vitamin D and 1,25(OH)2-Vitamin D are also indicated for those with advanced renal insufficiency (chronic kidney disease [CKD] Stage 3 or 4). All patients with underlying renal disease will need a lipid panel since they are at higher risk for cardiovascular disease.

Ultrasound

The diagnosis of ADPKD is established primarily with ultrasound images of the kidneys. The presence of different numbers of renal cysts based on the age of the patient, along with the presence of enlarged kidneys is unique to ADPKD. Both magnetic resonance imaging (MRI) (Figure 2) and CT (Figure 3) images can be used in ADPKD in the case of complications, such as pain, bleeding and infection. However, they are not used for diagnostic purposes. MRI-based determination of total kidney volume (TKV) is becoming a more and more important biomarker for the stage of ADPKD and the rate of progression. Although prognostic estimations can be made very reliably based on TKV, this is not (yet) the standard of care, and is mostly used as a research biomarker in clinical trials.

Figure 2.

Figure 3.

Kidney with simple and complex cyst. Contrast material-enhanced-CT scan shows a poorly enhancing solid lesion (arrowhead) on the posterior aspect of the right kidney and a small simple cyst (long arrow) anteriorly. The large cystic mass (thick arrow) on the posterolateral surface of the left kidney has a thick wall and numberous septa and is therefore considered indeterminate. Fluid in the cystic compartment of the lesion remained at water density. (From Marotti et al, Radiology 162:679-684, 1987, with permission.)

Mutation screening

Mutation screening using direct sequencing of the PKD1 or PKD2 genes is commercially available. Direct sequencing is the most accurate and reliable method but is expensive. Since the mutations are often unique to each family, less expensive exon-specific sequencing is available after one family member’s mutations are identified. Current mutation detection rate is 85% for the PKD1 gene and 95% for the PKD2 gene. Genetic testing remains as an essential tool for pre-symptomatic screening for young individuals or potential kidney donors.

Molecular testing

Molecular testing for prenatal diagnosis or pre-implantation diagnosis is also available for families whose members have an established mutation. From most mutation screening programs, the mutations described are scattered and are unique. Most mutations in either gene are single base changes or insertions or deletions of a small number of base pairs, resulting in truncated proteins and loss of protein function. Patients with mutations in the 5’ region have slightly more severe and more vascular disease than the 3’ region.

ADPKD has a large phenotypic variability among affected individuals, attributable to PKD genetic and allelic variability, modifier gene effects and environmental effects. Genetic effects are attributed to the PKD gene involved. As noted, PKD1 mutations are associated with more severe disease and earlier onset. PKD1 patients also have an earlier incidence of hypertension. Gender differences have been observed in PKD2 patients: men with PKD2 mutations progress to ESRD faster than women. No such difference is demonstrable for PKD1 patients.

Overall, an ADPKD diagnosis is mainly based on a family history and renal ultrasound screening. Genetic testing remains an essential tool for presymptomatic diagnosis in young individuals or potential kidney donors.

How should patients with ADPKD be managed?

Despite significant advances in the understanding of the genetics of ADPKD and the mechanism of cyst growth, no treatment specifically directed toward the disease is yet available. Current treatments focus on slowing the disease progression and reducing symptoms.

Poorly controlled hypertension accelerates the decline in renal function. Activation of the renin-angiotensin-aldosterone system (RAAS) in ADPKD has been confirmed by elevated plasma rennin activity and aldosterone in patients. Administration of an angiotensin converting enzyme (ACE) inhibitor to ADPKD patients resulted in a significantly greater decrease in renal vascular resistance and increase in renal plasma flow than in control group. Current recommendations for target blood pressure level and the initial drug of choice for ADPKD are based on the Seventh Joint National Committee (JNC7) recommendations for all patients with chronic kidney disease, targeting blood pressure below 130/80 mm Hg using ACE inhibitors or angiotensin receptor blockers (ARBs).

Results of the HALT-PKD trials suggest that rigorous blood pressure control with ACEI or ACEI/ARB combinations in early ADPKD may favourably alter the rate of renal function decline. Rigorous versus standard blood pressure targets were defined as 95/60-110/75 mm Hg versus 120/70-130/80 mm Hg, respectively. The measured positive renal outcomes of rigorous blood pressure control included a slower progression of total kidney volume and urinary albumin excretion, while a statistically significant change in eGFR was not observed in the study follow-up timeframe of 8 years. In addition, rigorous blood pressure control led to a greater decline in LV mass index than standard blood pressure control, which serves as a surrogate determinant of cardiovascular morbidity and mortality.

Studies of Vasopressin V2 receptor antagonists in a rat/murine model and human subjects show that they successfully slow renal cyst growth by inhibition of the V2 receptor, potentially reducing intracellular cAMP levels, resulting in decreased water reabsorption and urinary osmolality. The V2-receptor antagonist Tolvaptan, as compared with placebo, was shown to decrease the progression of total kidney volume and the worsening of renal function in a 3-year study timeframe, but adverse events from liver function test abnormalities, as well as aquaresis-related poor tolerability led to a higher rate of therapy discontinuation. As of now, Tolvaptan is not recommended for the therapy of ADPKD in the United States. A large quantity of fluid intake mimics the pharmacological inhibition of vasopressin mediated intracellular cAMP increase, and may be eventually beneficial.

Three major trials investigating mTOR inhibition in ADPKD with Sirolimus or Everolimus did not result in significant outcomes that could be clinically meaningful at this point. Future therapeutic studies are at various stages of clinical investigation, involving the substances bosutinib, tesevatinib, targeting various receptor and non-receptor-tyrosine kinases, as well as derivatives of the glucosylceramide synthetase inhibitor Genz-123346.

The best way to address sodium and phosphate is control dietary sodium and protein intake. Sometimes patients need dietary counseling. Closer lipid monitoring with regard to cholesterol level is also beneficial. Acidosis can be corrected by giving bicarbonate. Parathyroid hormone needs to be brought under control, otherwise the patient will have fragile bone and calcium deposits in their vessels.

Significant extrarenal manifestations, such as polycystic liver and intracranial aneurysm, may present in some ADPKD patients. Most polycystic liver patients are asymptomatic and require no treatment. In symptomatic individuals, therapy is directed toward reducing cyst volume and hepatic size. Options include therapy with somatostatin analogues, percutaneous cyst aspiration and sclerosis, laparoscopic fenestration, open surgical fenestration or even partial hepatectomy.

Procedures used to deal with intracranial aneurysms vary by the size. Intracranial aneurysm (ICA) cluster in ADPKD families and occur in 10% of individuals with a family history of an non-ruptured ICA and 20% of individuals with a family history of a ruptured ICA. While screening for the presence of ICA is not recommended solely on the basis of an ADPKD diagnosis, it is clearly recommended for those with a family member with an ICA, and also for those with uncertain family history or high-risk professions.

Asymptomatic aneurysms measuring less than 5 mm in diameter can be observed and followed at regular intervals (typically every 3 years). Any unruptured intracranial aneurysms larger than 10 mm are at high risk for rupture and should be subject to surgical or neuro-radiological intervention.

What happens to patients with ADPKD?

Kidney enlargement is a universal feature of ADPKD. Significant progression of cyst growth and kidney enlargement precedes the loss of kidney function in ADPKD. The multicenter study using magnetic resonance imaging (MRI) following ADPKD progression – the Consortium for Radiological Imaging in the study of Polycystic Kidney Disease (CRISP) – reported that total kidney volume is a strong predictor of future decline in GFR to CKD Stage 3. PKD1 patients demonstrated significantly larger kidney volumes, but with a similar rate of kidney growth between PKD1 and PKD2 (PKD1 5.68%/yr; PKD2 4.82%/yr). More cysts were detected in age matched PKD1 kidneys vs PKD2 kidneys, accounting for the differences seen in total kidney volumes seen.

The overall prevalence of hepatic cysts In the CRISP population was 83% (85% female and 79% males). Hepatic cysts increased in size and frequency with age; for instance, over 94% of patients 35 years and older demonstrating involvement. Importantly, hepatic cyst volume was significantly greater in women versus men.

ESRD occurs in 50% of ADPKD patients between the ages of 57-73, depending on the clinical series. Risk factors for progression to renal failure include total kidney volume, PKD1 mutation, male gender, diagnosis of ADPKD before age 30, hematuria episodes before age 30, and hypertension onset before age 35. Hyperlipidemia, low renal blood flow, low HDL and increased sodium intake are associated with increased total kidney volume that may result in progressive renal insufficiency.

Fertility rates in ADPKD patients not on dialysis are similar to the general population. Hypertensive ADPKD women have a higher incidence of worsening hypertension and preeclampsia during pregnancy and higher rate of premature delivery; while the normotensive woman’s outcome is similar to the general population.

How to utilize team care?

Specialty consultations

Genetic counseling: During the diagnosis procedure, a geneticist should explain to the family: linkage analysis of the disease which would require participation of other family members with and without the disease.

If ADPKD is diagnosed, the patient should receive counseling on family planning, understand the genetic risk for inheritance of an autosomal dominant disorder, and start to receive treatment if necessary. The patient should be told that each child of an affected person has a 50% chance of inheriting the disease gene. Each at-risk family member should be informed of the methods of diagnosis and of the availability of prenatal diagnosis. However, before a diagnostic test is performed, every subject also needs to be informed about the consequences of diagnostic screening, particularly regarding insurability, to permit informed judgment.

Nurses

Nurses should help with performing blood pressure checking, remind patient to take the right dose of medication, and assist physician-patient communication. Home blood pressure monitoring is an important feature of management/administration of required subcutaneous and intravenous medications such as erythropoietin will be supported by nurses.

Pharmacists

Conservative therapies known to slow the progression of kidney disease and those appropriate to treat the attendant manifestations of reduced kidney function (including hypertension, anemia, acidosis, and hyperparathyroidism), as well as metabolic and cardiovascular health (therapy of diabetes, hyperuricemia, dyslipidemia etc.) remain the standard of care. In case of growth retardation, appropriate methods should be employed.

Dietitians

Dietitians should help individuals with ADPKD understand the role of renal diet in helping to preserve kidney function, reducing the amount of phosphate, protein, sodium and acid in the diet.

Therapists (physical, occupational, speech, other)

Patients whose condition progresses to ESRD require renal replacement therapy and will need their nephrologists and transplant team to cooperates well for a successful transplant.

(The HALT-PKD A/B trials investigate single versus dual blood pressure control with ACEI or ACEI/ARB combination, in patients with ADPKD, including targeting standard versus rigorous blood pressure targets in patients with early stage ADPKD.)

(A remarkable study using Roscovitine in a murine model of polycystic kidney disease, giving rise to an emerging interest in proliferative/cell cycle and transcription regulation pathways as a therapeutic target in human ADPKD.)

(Authors presented renin-angiotensin-aldosterone system is stimulated significantly more in hypertensive patients with PKD and hypothesized that the increased renin release may contribute to the early development of hypertension in PKD.)

(Author studied renal hemodynamics and concluded the renal renin-angiotensin system plays a central role in the alterations in renal hemodynamics and sodium management associated with the development of hypertension in ADPKD.)